The present invention relates to a pharmaceutical composition for treating a symptom accompanied by non-intentional behavior, particularly for treating poriomania or hyperkinesia (including attention-deficit/hyperactive disorder; ADHD) and the use of running neuron inhibitory substance. For some vertebrates such as human, dog or cat, poriomania, especially poriomania and/or hyperkinesia occurring during the night, may cause some problems. Poriomania or hyperkinesia is generally believed to need psychiatric treatments. Particularly, poriomania of elderly person of advanced age was believed to be closely associated with Alzheimer""s disease. Such conditions often raise problems, because they not only cause harmful effects to the patients, especially to the patients suffering from other diseases but cause harmful effects to surrounding people. The term xe2x80x9cporiomaniaxe2x80x9d herein used means xe2x80x9cwandering from home driven by an abnormal impulsusxe2x80x9d or xe2x80x9ccausing an uncontrollable impulsus for wandering or travelingxe2x80x9d (see, for example, Stedman""s Medical Dictionary, revised 2nd edition, 1989, Medical View Publishing Company). The term xe2x80x9chyperkinesiaxe2x80x9d or xe2x80x9chyperkinetic syndromexe2x80x9d herein used is a general idea including a condition of a disease characterized by having abnormal excess energy and is believed to be a syndrome observed in a little child having a damage in the brain or having mental disability or during epilepsy, including the idea (see the aforementioned Medical Dictionary). Hyperkinesia has been believed to be characterized by excess motions and unstable emotion (see the aforementioned Medical Dictionary). It has been known that such a symptom is also observed for canine. As will be suggested by the foregoing description, the abnormal behaviors of these patients have been considered to be intentional ones.
Thus, antipsychotic drugs, somnifacients or muscle relaxants being capable of suppressing motions of patients have been generally used for treating patients in such conditions. However, these drugs newly cause several troubles, such as obnubilation or systemic muscular relaxation. Moreover, patients have sometimes been physically deprived of their liberty by inevitably binding patients to beds or by placing them in confinement as a symptomatic treatment for the poriomania and hyperkinesia, but the treatment would inflict considerable pain on these patients. In any event, conventionally known therapeutics or drugs has been focusing on preventing patients from freely movement or non-intentional movement, which may damage the quality of life of the patients.
On the other hand, independent of the foregoing clinical investigations, many attempts have been made, during the studies of neuron focused on the running activity, especially on the night running activity. For example, the inventors of the present invention reported that when the ventromedial nucleus of hypothalamus (hereinafter simply referred to as xe2x80x9cVMHxe2x80x9d) of rat was stimulated by water absorbent polymers, the running activity on rat was induced by the pressure stimulus (Yokawa, et. al., Physiology and behavior (1989), 46, 713-717). According to this report, signals from VMH were indicated to be required for the induction of running activity in rat, based on the observation that the running activity did not occur when VMH region had been excised from the animals. Additionally, the inventors demonstrated that the foregoing induction of rat running activity caused by polymers could be inhibited by administration of GABA (xcex3-aminobutyric acid) (Yokawa, et. al., Physiol. and Behav.(1990), 47, 1261-1264). The inventors also reported that the running activity in rat may be induced by a kind of ionotropic glutamate receptor, kainate receptor agonists (Narita, et. al., Brain Res. (1993), 603, 243-247). According to the report, the running activity in rat was induced by kainate and was not inhibited by GABA but the running activity was inhibited by DNQX(6,7-dinitroquinoxaline-2,3-dione), a kainate receptor antagonist, which suggest that the neuron controlling the running activity in rat may be stimulated through kainate receptors and that GABAA receptors presynaptically inhibit the neuron controlling the running activity in rat against the kainate receptors. On the other hand, it has been also reported that substances having the competitive inhibitory activity against GABAB receptors are likewise useful in treatment of neurological disease accompanied by convulsion, Alzheimer""s disease or memory retention disorder (Japanese unexamined publication, JP 4-243853).
The object of the present invention is to provide a pharmaceutical composition which suppresses non-intentional locomotion but do not suppress intentional locomotion. Particularly, the object of the present invention is to provide a pharmaceutical composition for treating diseases including poriomania or hyperkinesia.
The object of the present invention is also to provide a method of treating symptoms accompanied by non-intentional behaviors, comprising the step of administrating the one or more running neuron inhibitory substances or the pharmaceutical composition of the present invention.
The another object of the present invention is to provide the use of running neuron inhibitory substances for producing such pharmaceutical compositions. The inventors have been suggested that there are some neurons in the VMH which were strongly suggested to be involved in the running activity in rat, especially in the night running activity, as previously mentioned. The inventors designated the neuron existing in the VMH region as xe2x80x9crunning neuronxe2x80x9d and concluded that the running neuron is the neuron which regulate the non-intentional locomotion in rat. The hypothalamic region, including the VMH, is believed to be well conserved among vertebrates and the hypothalamic region is phylogenically one of the oldest parts of the central nerve system. Therefore, we propose that the running neuron that we described herein in rats exist also in the VMH region of other vertebrate animals, including humans and canine. Furthermore, it is clinically observed that patients exhibiting poriomania usually give an unreasonable explanation or they say that they forgot the aim of wandering or they had not the intention of wandering. Additionally, hyperkinesia is clinically believed to be an intentional behavior. The inventors took these findings into account and became to believe that the running neuron must exists in other animals than rat such as human and dog, and to associate the input from the neuron with certain behaviors including poriomania and hyperkinesia, from the point of view that poriomania or hyperkinesia in human and certain vertebrates is a xe2x80x9cnon-intentional behaviorxe2x80x9d rather than an xe2x80x9cintentional behaviorxe2x80x9d as previously believed. Consequently, the inventors led to invent the pharmaceutical composition and the method, which may inhibit certain behaviors including poriomania and hyperkinesia, but do not inhibit intentional locomotion. Thus, the present invention is a pharmaceutical composition for treating a symptom accompanied by non-intentional behaviors including poriomania and hyperkinesia, which comprises a substance being able to inhibit the running neuron in the presynaptic or postsynaptic manner.
The present invention comprises also the use of a substance being able to inhibit the running neuron in the presynaptic or postsynaptic manner for producing a pharmaceutical composition for treating a symptom accompanied by non-intentional behaviors including poriomania and hyperkinesia.
Particularly, the present invention is a pharmaceutical composition for treating a symptom accompanied by non-intentional behaviors, including poriomania and hyperkinesia. The composition comprises substances selected from the group consisting of GABAB receptor agonists, GABAA receptor agonists, or substances that enhance the activity of GABAA receptor and kainate receptor antagonists, or any combination thereof. The present invention comprises also the use of such substances for producing a pharmaceutical composition for treating a symptom accompanied by non-intentional behaviors including poriomania and hyperkinesia.